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Title: Potent and broad HIV-neutralizing antibodies in memory B cells and plasma

Abstract

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1–specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1–infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains. external region (MPER) have extensive neutralization breadth, and one of these, 10E8, reactive to the distal MPER, is one of the most broadly reactive HIV-1–neutralizing antibodies isolated to date (1–3). Two other MPER-binding gp41 bnAbs, 2F5 and 4E10, are both polyreactive, and their expression is limited by immune tolerance control in bnAbmore » knock-in mice (4–7). In contrast, the 10E8 bnAb, in addition to potency and breadth, has lower reactivity with host molecules than 2F5 and 4E10 (1, 8–10). Thus, vaccine strategies for induction of 10E8-like antibodies are key to the development of an HIV-1 vaccine that can induce multiple broad and potent neutralizing antibody specificities. Here, we have isolated a clonal lineage (DH511) of broad and potent Env gp41 distal MPER bnAbs from both memory B cells and plasma from an HIV-1–infected African individual, defined the DH511 developmental pathway, and demonstrated the reactivity of the DH511 unmutated common ancestor (UCA) with the A subunit of the autoantigen ribonucleoprotein (RNP), providing a mechanism of bnAb induction. Finally, plasma DH511 bnAb lineage members were equally as potent neutralizers of HIV-1 as were bnAbs derived from memory B cells. Moreover, a chimeric DH511 lineage antibody consisting of memory bnAb VH [variable region of immunoglobulin (Ig) heavy chain] and plasma bnAb VL (variable region of Ig light chain) was broader than 10E8 and neutralized 99% of the HIV-1 isolates tested.« less

Authors:
 [1];  [2];  [3];  [3];  [1];  [1];  [4];  [2];  [1];  [5];  [5];  [5];  [5];  [6];  [7];  [1];  [1];  [1];  [1];  [1] more »;  [8];  [9];  [10];  [10];  [11];  [1];  [12];  [13];  [14];  [1];  [1];  [1];  [1];  [1];  [5];  [1];  [1];  [1];  [1];  [3];  [1] « less
+ Show Author Affiliations
  1. Duke Univ. School of Medicine, Durham, NC (United States)
  2. Univ. of Maryland, Rockville, MD (United States)
  3. Univ. of Texas, Austin, TX (United States)
  4. Univ. of Maryland, Rockville, MD (United States
  5. National Inst. of Health (NIH), Bethesda, MD (United States)
  6. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  7. Harvard Medical School, Boston, MA (United States)
  8. National Inst. for Communicable Diseases, Johannesburg (South Africa)
  9. Univ. of KwaZulu-Natal, Congella (South Africa). Nelson R. Mandela School of Medicine
  10. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  11. Boston Univ. School of Medicine, Boston, MA (United States)
  12. National Inst. for Communicable Diseases, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Congella (South Africa). Nelson R. Mandela School of Medicine
  13. Univ. of North Carolina Project-Malawi, Lilongwe (Malawi)
  14. Univ. of North Carolina, Chapel Hill, NC (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1460631
Report Number(s):
LA-UR-16-29055
Journal ID: ISSN 2470-9468
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Science Immunology
Additional Journal Information:
Journal Volume: 2; Journal Issue: 7; Journal ID: ISSN 2470-9468
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

Williams, LaTonya D., Ofek, Gilad, Schatzle, Sebastian, McDaniel, Jonathan R., Lu, Xiaozhi, Nicely, Nathan I., Wu, Liming, Lougheed, Caleb S., Bradley, Todd, Louder, Mark K., McKee, Krisha, Bailer, Robert T., O'Dell, Sijy, Georgiev, Ivelin S., Seaman, Michael S., Parks, Robert J., Marshall, Dawn J., Anasti, Kara, Yang, Guang, Nie, Xiaoyan, Tumba, Nancy L., Wiehe, Kevin, Wagh, Kshitij, Korber, Bette, Kepler, Thomas B., Munir Alam, S., Morris, Lynn, Kamanga, Gift, Cohen, Myron S., Bonsignori, Mattia, Xia, Shi-Mao, Montefiori, David C., Kelsoe, Garnett, Gao, Feng, Mascola, John R., Moody, M. Anthony, Saunders, Kevin O., Liao, Hua-Xin, Tomaras, Georgia D., Georgiou, George, and Haynes, Barton F. Potent and broad HIV-neutralizing antibodies in memory B cells and plasma. United States: N. p., 2017. Web. doi:10.1126/sciimmunol.aal2200.
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Williams, LaTonya D., Ofek, Gilad, Schatzle, Sebastian, McDaniel, Jonathan R., Lu, Xiaozhi, Nicely, Nathan I., Wu, Liming, Lougheed, Caleb S., Bradley, Todd, Louder, Mark K., McKee, Krisha, Bailer, Robert T., O'Dell, Sijy, Georgiev, Ivelin S., Seaman, Michael S., Parks, Robert J., Marshall, Dawn J., Anasti, Kara, Yang, Guang, Nie, Xiaoyan, Tumba, Nancy L., Wiehe, Kevin, Wagh, Kshitij, Korber, Bette, Kepler, Thomas B., Munir Alam, S., Morris, Lynn, Kamanga, Gift, Cohen, Myron S., Bonsignori, Mattia, Xia, Shi-Mao, Montefiori, David C., Kelsoe, Garnett, Gao, Feng, Mascola, John R., Moody, M. Anthony, Saunders, Kevin O., Liao, Hua-Xin, Tomaras, Georgia D., Georgiou, George, & Haynes, Barton F. Potent and broad HIV-neutralizing antibodies in memory B cells and plasma. United States. https://doi.org/10.1126/sciimmunol.aal2200
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Williams, LaTonya D., Ofek, Gilad, Schatzle, Sebastian, McDaniel, Jonathan R., Lu, Xiaozhi, Nicely, Nathan I., Wu, Liming, Lougheed, Caleb S., Bradley, Todd, Louder, Mark K., McKee, Krisha, Bailer, Robert T., O'Dell, Sijy, Georgiev, Ivelin S., Seaman, Michael S., Parks, Robert J., Marshall, Dawn J., Anasti, Kara, Yang, Guang, Nie, Xiaoyan, Tumba, Nancy L., Wiehe, Kevin, Wagh, Kshitij, Korber, Bette, Kepler, Thomas B., Munir Alam, S., Morris, Lynn, Kamanga, Gift, Cohen, Myron S., Bonsignori, Mattia, Xia, Shi-Mao, Montefiori, David C., Kelsoe, Garnett, Gao, Feng, Mascola, John R., Moody, M. Anthony, Saunders, Kevin O., Liao, Hua-Xin, Tomaras, Georgia D., Georgiou, George, and Haynes, Barton F. Fri . "Potent and broad HIV-neutralizing antibodies in memory B cells and plasma". United States. https://doi.org/10.1126/sciimmunol.aal2200. https://www.osti.gov/servlets/purl/1460631.
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@article{osti_1460631,
title = {Potent and broad HIV-neutralizing antibodies in memory B cells and plasma},
author = {Williams, LaTonya D. and Ofek, Gilad and Schatzle, Sebastian and McDaniel, Jonathan R. and Lu, Xiaozhi and Nicely, Nathan I. and Wu, Liming and Lougheed, Caleb S. and Bradley, Todd and Louder, Mark K. and McKee, Krisha and Bailer, Robert T. and O'Dell, Sijy and Georgiev, Ivelin S. and Seaman, Michael S. and Parks, Robert J. and Marshall, Dawn J. and Anasti, Kara and Yang, Guang and Nie, Xiaoyan and Tumba, Nancy L. and Wiehe, Kevin and Wagh, Kshitij and Korber, Bette and Kepler, Thomas B. and Munir Alam, S. and Morris, Lynn and Kamanga, Gift and Cohen, Myron S. and Bonsignori, Mattia and Xia, Shi-Mao and Montefiori, David C. and Kelsoe, Garnett and Gao, Feng and Mascola, John R. and Moody, M. Anthony and Saunders, Kevin O. and Liao, Hua-Xin and Tomaras, Georgia D. and Georgiou, George and Haynes, Barton F.},
abstractNote = {Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1–specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1–infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains. external region (MPER) have extensive neutralization breadth, and one of these, 10E8, reactive to the distal MPER, is one of the most broadly reactive HIV-1–neutralizing antibodies isolated to date (1–3). Two other MPER-binding gp41 bnAbs, 2F5 and 4E10, are both polyreactive, and their expression is limited by immune tolerance control in bnAb knock-in mice (4–7). In contrast, the 10E8 bnAb, in addition to potency and breadth, has lower reactivity with host molecules than 2F5 and 4E10 (1, 8–10). Thus, vaccine strategies for induction of 10E8-like antibodies are key to the development of an HIV-1 vaccine that can induce multiple broad and potent neutralizing antibody specificities. Here, we have isolated a clonal lineage (DH511) of broad and potent Env gp41 distal MPER bnAbs from both memory B cells and plasma from an HIV-1–infected African individual, defined the DH511 developmental pathway, and demonstrated the reactivity of the DH511 unmutated common ancestor (UCA) with the A subunit of the autoantigen ribonucleoprotein (RNP), providing a mechanism of bnAb induction. Finally, plasma DH511 bnAb lineage members were equally as potent neutralizers of HIV-1 as were bnAbs derived from memory B cells. Moreover, a chimeric DH511 lineage antibody consisting of memory bnAb VH [variable region of immunoglobulin (Ig) heavy chain] and plasma bnAb VL (variable region of Ig light chain) was broader than 10E8 and neutralized 99% of the HIV-1 isolates tested.},
doi = {10.1126/sciimmunol.aal2200},
journal = {Science Immunology},
number = 7,
volume = 2,
place = {United States},
year = {Fri Jan 27 00:00:00 EST 2017},
month = {Fri Jan 27 00:00:00 EST 2017}
}
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Journal Article:
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https://doi.org/10.1126/sciimmunol.aal2200
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Figures / Tables:

Fig. 1 Fig. 1: Isolation of MPER-directed bnAbs (A) Fluorescently labeled MPR.03 peptide tetramers were used to decorate PBMCs from donor CH0210. A flow cytometric plot is shown. The square represents frequency of MPR. 03 double-positive MPER-specific memory B cells that were sorted for Ig gene amplification and expression. Colored dots withinmore » the square show individual cells that yielded MPER-specific mAbs DH511.1 to DH511.6 and DH517, as revealed by index sorting. Memory B cells were gated as live CD16−CD14−CD3−CD235−CD19+IgD−/ CD38all. (B) Phylogenetic tree of VHDHJH sequences of the DH511 clonal lineage. Ancestral reconstruction of the evolutionary pathway from the inferred UCA to the mature mAbs including six maturational intermediates (I1 to I6, circles). DH511.13 could not be expressed and was not studied further. (C) Neutralization activity of probe-identified MPER antibodies against a panel of 208 cross-clade HIV-1 isolates. Median and geometric mean neutralization potency against viruses neutralized with an IC50/IC80 of <50 μg/ml. Right: The percentage of 208 viruses neutralized by mAbs DH511.2, 10E8, and VRC01 at IC50 or IC80 of <50 μg/ml, <1 μg/ml, and <0.1 μg/ml. (D) Neutralization potency and breadth of DH511.2 compared with 10E8 and VRC01 against a 208-isolate HIV-1 Env pseudovirus panel displayed as potency-breadth curves. The percentage of isolates neutralized at IC50 (top) and IC80 (bottom) values is plotted against mAb concentration. (E) Percent maximum neutralization of each isolate by DH511.2. (F) Identification of MPER-directed broadly neutralizing plasma antibodies by proteomics. Phylogenetic tree of heavy chain sequences identified in the plasma and added to DH511.1 to DH511.6 isolated from the memory B cell compartment [see (B)]. The bar on the right shows the relative abundance of the three identified clonotypes in serum (IV, 95%; II, 4%; III, 1%).« less
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  • J., Eron, Joseph; A., Vandergrift, Nathan; Hua-Xin, Liao,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/2tyg-me06

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  • K., Wibmer, C.; M., Shaw, G.; T., Tong,
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  • F., Haynes, Barton; M., Lynch, Rebecca; Xiaozhi, Lu,
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  • N., Denny, Thomas; J., Marshall, Dawn; Eleanor, Marshal,
  • The University of North Carolina at Chapel Hill University Libraries
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  • Hongmei, Gao,; Tanmoy, Bhattacharya,; S., Cohen, Myron
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/py3f-pj09
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